This invention relates to heteroarylpiperidines, pyrrolidines and piperazines. More particularly, this invention relates to heteroarylpiperidines, pyrrolidines and piperazines having antipsychotic activity and to their use as antipsychotic drugs.
The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued. There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses.
Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs include the so-called extrapymmidal symptoms, such as rigidity and tremor, continuous restless walking, and tardive dyskinesia which causes facial grimacing, and involuntary movements of the face and extremities. Orthostatic hypotension is also common. Thus, there also exists a need in the art for antipsychotic drugs that produce fewer or less severe manifestations of these common side effects.
In addition, because of the frequent long term administration of neuroleptics and the problems with patient compliance, there is a further need in the art for long lasting neuroleptics, which can be formulated into sustained release depot preparations, without the side effects previously mentioned.
Moreover, there has been a need for drugs that can produce other biological effects. For example, relief from pain has been an age-old aspiration which has led to the discovery of natural and synthetic anagletics. Nevertheless, the need for safe and effective analgetics has continued to the present day.
This invention aids in fulfilling these needs in the art by providing a compound of the formula: 
wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(R2)xe2x80x94,
R2 is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl and phenylsulfonyl groups;
p is 1 or 2;
Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;
Q1 is selected from the group consisting of: 
where Z is 
and Y2 is selected from the group consisting of: 
xe2x80x83in which (R1) is xe2x80x94CR24R27xe2x80x94(CR23R24)nxe2x80x94CR24R27xe2x80x94 where n is 0,1,2, or 3; or xe2x80x94CHR24CHxe2x95x90CHxe2x80x94CHR24xe2x80x94, xe2x80x94CHR24xe2x80x94Cxe2x89xa1Cxe2x80x94CHR24xe2x80x94, xe2x80x94CHR24xe2x80x94CHxe2x95x90CHxe2x80x94CR23R24xe2x80x94CHR24xe2x80x94, xe2x80x94CHR24xe2x80x94CR23R24xe2x80x94CHxe2x89xa1CHxe2x80x94CHR24xe2x80x94, xe2x80x94CHR24xe2x80x94Cxe2x95x90Cxe2x80x94CR23R24xe2x80x94CHR24xe2x80x94, or xe2x80x94CHR24xe2x80x94CR23R24xe2x80x94Cxe2x89xa1Cxe2x80x94CHR24xe2x80x94, the xe2x80x94CHxe2x95x90CHxe2x80x94 bond being cis or trans;
R and m are as defined hereinafter;
R23 is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy, alkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkyl oxy lower alkyl, alkanoyloxy lower alkyl or 
xe2x80x83where Z1 is lower alkyl, xe2x80x94OH, lower alkoxy, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94NH2 or halogen; and
R24 is hydrogen, alkyl, aryl, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkoxy lower alkyl, alkanoyloxy lower alkyl or 
xe2x80x83where Z1 is as previously defined:
R27 is hydrogen or R24 and R27 taken together with the carbon to which they are attached form Cxe2x95x90O or Cxe2x95x90S;
and R and m are as defined hereinafter: 
xe2x80x83where R1 is as previously defined, and R3 is hydrogen or xe2x80x94OCH3: 
xe2x80x83where R1 is as previously defined; and
R4 is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C1-C6)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C1-C18)acyl amino, (C1-C18)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18 straight or branched chain) alkyl or xe2x80x94C(xe2x95x90O)-aryl;
in which aryl is phenyl or 
where R5 is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; 
where R1 and R4 are as previously defined; 
where either one of Xy or Xz is xe2x80x94C(xe2x95x90O)xe2x80x94 and the other is xe2x80x94CH2xe2x80x94; and
R5xe2x80x2 is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and
R1 is as previously defined: 
where R1 and R4 are as previously defined; 
where A is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x95x90CH2)xe2x80x94, xe2x80x94C(xe2x95x90O)CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CR26xe2x95x90Nxe2x80x94, or xe2x80x94CR25R26xe2x80x94;
R25 is hydrogen, lower alkyl, hydroxy or alkanoyloxy;
R26 is hydrogen or lower alkyl;
either one of By and Bz is CH or N and the other is CH;
U is O or S;
q is 1,2,3 or 4, and R1 and R4 are as previously defined: 
where R1 is as previously defined; 
wherein R1, R4 and q are as defined above; and
R28 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl or substituted phenyl; 
wherein R1, R4 and q are as defined above;
R29 and R30 are hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl or substituted phenyl;
R31 and R32 are hydrogen, hydroxy, (C1-C6)alkyl, aryl(C1-C6)alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHOR33 where R33 is (C1-C18)alkanoyl; or
either R29 and R30 taken together or R31 and R32 taken together with the carbon group to which they are attached from a Cxe2x95x90O or Cxe2x95x90S group; 
where R1, R4, R28, R29, R30, R31, R32 and q are as defined above: 
where R1, R4, R28, R29, R30, R31, R32 and q are as defined above; 
wherein R1 and R4 are previously defined and m is defined hereinafter: 
wherein R1 is as previously defined;
Q2 is S, NH, or xe2x80x94CH2xe2x80x94; and
R and m are as defined hereinafter: 
where R1 is as previously defined; 
where R1, and R4 are as previously defined and m is as defined hereinafter: 
where R1, R4 are as previously defined and m is as defined hereinafter:
xe2x80x94R1xe2x80x94Oxe2x80x94R12xe2x80x83xe2x80x83(18) 
where R12 is selected from the group consisting of:
hydrogen,
alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18 straight chain or branched)alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94NR13R14,
xe2x80x94C(xe2x95x90O)xe2x80x94NR15R16,
xe2x80x94S(xe2x95x90O)2xe2x80x94R17, and 
where R13 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where R14 is selected from the group consisting of hydrogen and (C1-C18)alkyl groups;
where NR15R16 taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R17 is selected from the group consisting of lower alkyl and aryl groups;
where R4 is previously defined and m is defined hereinafter:
xe2x80x94R1xe2x80x94NR18R19xe2x80x83xe2x80x83(19) 
where R1r and R1v are independently selected from the group consisting of:
hydrogen,
(C1-C12 straight or branched chanin)alkyl;
xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(C1-C18)alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C18)alkyl;
xe2x80x94C(xe2x95x90O)-pyridyl or 
where NR18R19 taken togther form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl: where the piperidinyl or piperazinyl ring is optionally substituted by 
where R1, X, Y, p, R4 and R28 are as previously defined and m is defined hereinafter:
xe2x80x94R1xe2x80x94Sxe2x80x94R12xe2x80x83xe2x80x83(20) 
where R1 and R12 are as previously defined; 
where R1, R4 and R28 are as previously defined; and where
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxy, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl,
xe2x80x94C(xe2x95x90O)-alkyl,
xe2x80x94C(xe2x95x90O)xe2x80x94O-alkyl,
xe2x80x94(Cxe2x95x90O)-aryl,
xe2x80x94C(xe2x95x90O)-heteroaryl,
xe2x80x94CH(OR7)-alkyl,
xe2x80x94C(xe2x95x90W)-alkyl,
xe2x80x94C(xe2x95x90W)-aryl, and
xe2x80x94C(xe2x95x90W)-heteroaryl;
alkyl is (C1-C18)alkyl;
aryl is as previously defined;
heteroaryl is 
Q3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94;
W is CH2 or CHR8 or Nxe2x80x94R9;
R7 is hydrogen, alkyl, or alkanoyl;
R8 is lower alkyl;
R9 is hydroxy, alkoxy, or xe2x80x94NHR10; and
R10 is hydrogen, alkyl, (C1-C3)acyl, aryl, xe2x80x94C(xe2x95x90O)aryl or xe2x80x94C(xe2x95x90O)heteroaryl, where aryl and heteroaryl are as defined above; and
m is 1, 2, or 3;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy or trifluoromethyl, and p is 1 or 2;
with the proviso that in formula (4) R4 is not H when R1 is xe2x80x94(CH2)2-5xe2x80x94, Z is not 
xe2x80x83X is xe2x80x94Sxe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl, and p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or trifluoromethyl and Q2 is xe2x80x94CH2xe2x80x94;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Oxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, lower alkyl, lower alkoxy, hydroxy or halogen, and p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2, R is hydrogen, and m is 1;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94N(R2)xe2x80x94, Q2 is xe2x80x94CH2xe2x80x94, R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkyl thio, lower mono- or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R2 is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;
with the proviso that in formula (14) Z is not 
xe2x80x83when X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94, where R2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2 and Q2 is xe2x80x94CH2xe2x80x94;
with the proviso that Y2 is not the moiety of formula (8) when Z is 
xe2x80x83X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (1) Z is not 
xe2x80x83when X is O or S, Y is hydrogen, R is hydrogen, (C1-C4)alkyl, chlorine, fluorine, bromine, iodine, cyano, (C1-C4)alkoxy, aryl, xe2x80x94COOR25 where R25 is (C1-C4)alkyl;
with the proviso that in formula (1) Z is not 
xe2x80x83when X is xe2x80x94Sxe2x80x94, R1 is xe2x80x94(CH2)2-5xe2x80x94, R is H, and m=1;
with the proviso that in formula (7) R4 is not hydrogen when Y is 6-F, X is xe2x80x94Oxe2x80x94, Z is 
xe2x80x83and n is 2, 3 or 4;
with the proviso that in formula (18) R12 is not H when Z is 
xe2x80x83X is xe2x80x94NHxe2x80x94 or xe2x80x94N(R2)xe2x80x94 where R2 is lower alkyl, aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is 1 or 2;
with the proviso that in formula (18), R12 is not H when X is xe2x80x94N(R2)xe2x80x94, where R2 is phenyl, Z is 
xe2x80x83and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (19), R18 and R19 are not lower alkyl when Z is 
xe2x80x83X is xe2x80x94N(R2)xe2x80x94 and R2 is aryl and Y is hyrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;
with the proviso that in formula (19), when X is xe2x80x94Oxe2x80x94, Z is 
xe2x80x83and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R18 and R19 are not lower alkyl;
with the proviso that in formula (19), R18 and R19 are not hydrogen when R1 is xe2x80x94(CH2)2-5xe2x80x94, Z is 
xe2x80x83X is xe2x80x94Oxe2x80x94, and Y is 6-F;
all geometric, optical and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.
This invention also provides compounds selected from formula 1 which are suitable for acylation with (C4-C18)carboxylic acids or reactive functional derivatives thereof to form highly lipophilic esters, amides and carbamates, which compounds are also compounds of this invention. Such selected compounds possess a hydroxyl group attached to either an aliphatic or aromatic carbon atom capable of forming the highly lipophilic esters of the invention, a primary or secondary nitrogen atom including the nitrogen at the 1-position of an indazole ring system capable of forming the highly lipophilic amides of the invention. The primary or secondary nitrogen atom may alternatively be acylated with a (C4-C18)alkoxycarbonyl chloride to form a highly lipophilic carbamatic derivative of the invention.
The invention also provides for the highly lipophilic compounds which provide long acting pharmaceutical effects when administered in the form of depot preparations.
This invention also provides a pharmaceutical composition, which comprises a compound of the invention and a pharmaceutically acceptable carrier therefor. In one embodiment of the invention, the pharmaceutical composition is an antipsychotic composition comprising a compound of the invention in an amount sufficient to produce an antipsychotic effect.
In addition, this invention provides a method of treating psychoses, which comprises administering to a patient a pharmaceutically effective amount of a compound of the invention.
Further, this invention provides a method of sustained release of a pharmaceutically effective amount of a lipophilic compound of the invention in the form of a depot preparation.
Finally, this invention provides a method of alleviating pain by administering to a patient a pain-relieving amount of a compound of the invention.